A major goal in solid organ transplantation is the engraftment of the donor organ without a graft rejection immune response generated by the recipient, while preserving the immunocompetence of the recipient against other foreign antigens. Typically, nonspecific immunosuppressive agents such as cyclosporine, methotrexate, steroids and FK506 are used to prevent host rejection responses. They must be administered on a daily basis and if stopped, graft rejection usually results. However, nonspecific immunosuppressive agents function by suppressing all aspects of the immune response, thereby greatly increasing a recipient's susceptibility to infections and diseases, including cancer.
Furthermore, despite the use of immunosuppressive agents, graft rejection still remains a major source of morbidity and mortality in human organ transplantation. Only 50% of heart transplants survive 5 years and 20% of kidney transplants survive 10 years. (See Powles, 1980, Lancet, p. 327; Ramsay, 1982, New Engl. J. Med., p. 392). Most human transplants fail within 10 years without permanent acceptance. It would therefore be a major advance if tolerance can be induced in the recipient.
The only known clinical condition in which complete systemic donor-specific transplantation tolerance occurs reliably and reproducibly is when chimerism is created through bone marrow transplantation. (See Qin et al., 1989, J. Exp. Med. 169:779; Sykes et al., 1988, Immunol. Today 9:23; Sharabi et al., 1989, J. Exp. Med. 169:493). This has been achieved in neonatal and adult animal models as well as in humans by total lymphoid irradiation of a recipient followed by bone marrow transplantation with donor cells. The widespread application of bone marrow transplantation to areas outside of malignancy has been limited by graft-versus-host disease (GVHD). The success rate of bone marrow transplantation is, in part, dependent on the ability to closely match the major histocompatibility complex (MHC) of the donor cells with that of the recipient cells. The MHC is a gene complex that encodes a large array of individually unique glycoproteins expressed on the surface of both donor and host cells that are the major targets of transplantation rejection immune responses. In the human, the MHC is referred to as HLA. When HLA identity is achieved by matching a patient with a family member such as a sibling, the probability of a successful outcome is relatively high, although GVHD is still not completely eliminated. The incidence and severity of GVHD are directly correlated with degree of genetic disparity. In fact, only one or two antigen mismatch is acceptable because GVHD is very severe in cases of greater disparities. When allogeneic bone marrow transplantation is performed between two MHC-mismatched individuals of the same species, common complications involve failure of engraftment, poor immunocompetence and a high incidence of GVHD.
GVHD is a potentially lethal complication in bone marrow transplantation, which occurs in about 35-50% of recipients of untreated HLA-identical marrow grafts (Martin et al., 1985, Blood 66:664) and up to 80% of recipients of HLA-mismatched marrow. Unfortunately, only 30% of patients generally have a suitably matched HLA-identical family member donor, and thus most patients are either excluded from being considered for bone marrow transplantation, or if they are transplanted must tolerate a high risk of GVHD. GVHD results from the ability of immunocompetent mature immune cells (mainly T cells, but some B cells and natural killer cells) in the donor graft to recognize host tissue antigens as foreign and invoke an adverse immunologic reaction. Although mixed allogeneic reconstitution, in which a mixture of donor and recipient marrow is transplanted, results in improved immunocompetence and increased resistance to GVHD, successful engraftment is still not consistently achieved and GVHD still often occurs.
Recent studies in bone marrow transplantation suggest that the major cause of GVHD are T-cells, as the removal of T cells from the donor cell preparation was associated with a reduction in the incidence of GVHD. (Vallera et al., 1989, Transplant, 47:751; Rayfield, 1984, Eur. J. Immunol., P. 308; Vallera, 1982, J. Immunol., 128:871; Martin and Korngold, 1978, J. Exp. Med., p 1687; Prentice, 1984, Lancet P. 472). After T-cells were implicated to be the predominant mediator of GVHD in animal models, aggressive protocols for T-cell depletion (TCD) of human donor bone marrow were instituted. Although the incidence of GVHD was decreased dramatically, TCD was accompanied by a significant increase in the failure of engraftment, indicating that T cells might also play a positive role in bone marrow engraftment. (Soderling, J. Immunol., 1985, 135:941; Vallera, 1982, Transplant. 33:243; Pierce, 1989, Transplant., p. 289). The increase in failure of engraftment in human recipients ranged from about 5-70% of total patients and was related to the degree of MHC disparity between the donor and recipient (Blazar, 1987, UCLA Symp., p. 382; Filipovich, 1987, Transplant., p. 62; Martin et al., 1985, Blood 66:664; Martin et al., 1988, Adv. Immunol. 40:379). Patients with failed engraftment usually die even if a second bone marrow transplant is performed. Consequently, most transplant institutions in the United States have abandoned TCD of donor bone marrow and, thus, must tolerate a high level of GVHD which leads to significant morbidity and mortality. Thus, the application of bone marrow transplantation as a form of treatment is limited only to settings where the potential of GVHD is clearly outweighed by the potential benefit. It was therefore anticipated that the administration of purified bone marrow stem cells would optimize engraftment and avoid GVHD. However, recent studies have shown that purified bone marrow stem cells only engraft in genetically identical, but not in genetically disparate recipients.
The implication that T cells might participate in both harmful GVHD reactions and helpful engraftment facilitation was an enigma that existed for a long time in the scientific community. Investigators began to search for the possible existence of a bone marrow component which could facilitate bone marrow engraftment but was removed during TCD. Identification and purification of this facilitating component would potentially allow the design of transplant protocols to selectively prevent GVHD, while preserving the cells that can enhance engraftment.
Although most investigators speculated that the facilitating component was a hematopoietic cell distinct from the hematopoietic stem cells, such a component had never been identified or characterized until recently. In fact, all evidence pointed towards the involvement of some form of T cells. It was recently discovered that a cell population referred to as FC facilitates engraftment of hematopoietic stem cells in a recipient without producing GVHD, and this cell expresses several markers shared by other leukocytes. The identification of specific markers expressed by FC would greatly assist the rapid isolation of this cell type.